The human BCR gene on chromosome 22 is specifically involved in the Philadelphia translocation, t(9; 22), a chromosome rearrangement present in the leukemic cells of patients with chronic myeloid leukemia (CML) or acute lymphoblastic leukemia (ALL). In most cases, the breakpoints on chromosome 22 are found within a 5.8 kb region of DNA designated the major breakpoint cluster region (Mbcr) of the BCR gene. Hybridization experiments have indicated that the human genome contains sequences related to the BCR gene. Heisterkamp et al. (1989, Nucl. Acids Res. 17: 8821-8831) have reported the cloning of one of these BCR-related sequences, termed ABR, located on chromosome 17p. ABR was reported (Id.) to be a functionally active gene containing exons very similar to those found within the Mbcr. ABR was also found (Id.) to exhibit great genomic variability associated with two different variable tandem repeat (VTR) regions located within two introns.
ABR appears to contain five small exons with a deduced amino acid sequence very similar to exons 1-5 of the Mbcr. ABR and BCR differ dramatically in one aspect: the BCR gene, although specifically involved in chromosomal translocations, was not particularly difficult to clone and does not appear to be genetically unstable. The gene has not been observed to vary in length among DNA samples from normal individuals, except for a polymorphism in the first intron (Rubin et al., 1988, Nucl. Acids Res. 16: 8741). In contrast, cloned segments of the ABR gene have been found to be highly unstable when propagated in E. coli, and a large number of different-sized alleles were found to exist in the general human population.
The variable tandem repeat regions, termed VTR-A and VTR-B, are located in ABR introns. VTR-A, within an intron 5' to the Mbcr homologous exons, appears to be the largest source of variability. VTR-B is located between Mbcr homologous exons 3 and 4. Interestingly, the location of this VTR corresponds to the Mbcr region highly prone to rearrangement in CML. Hybridization of a VTR-B probe to blots containing the cloned Mbcr region has failed to detect homologous regions.
Hypervariable regions have been described previously, either alone or in association with genes and the VTR regions described above fit the general patterns. For example, hypervariable regions consisting of 36, 14 and 17 bp tandem arrays have been found as interzeta, zeta-intron and alpha-globin 3 repeats (Goodbourn et al., 1983, Proc. Natl. Acad. Sci. U.S.A. 80: 5022-5026; Proudfoot et al, 1982, Cell 31:533-563; Jarman et al., 1986, EMBO J. 5: 1857-1863). Minisatellites from the insulin and Ha-rasl loci (Bell et al., 1982, Nature 295: 31-35, Capon et al., 1983, Nature 302: 33-37) have also been characterized and they can be used as chromosome-specific single copy probes. Abnormally high rates of genetic exchange have been observed in vivo and in vitro and it has been suggested that VTRs may promote such recombination events (Jeffreys et al., 1985, Nature 314: 67-73). They may operate as enhancer elements or in the organization of chromosome structure.